The Central Dogma of Molecular Biology

A paradigm is an example or pattern that "everyone" agrees upon which describes some concept. The paradigm of Molecular Biology is The Central Dogma. This hypothesis was described by Crick in 1958. In 1953, Watson and Crick were the first to determine the true crystaline structure of DNA (although there had been some competing theories before them), using model building and then X-ray crystallography. Once the DNA structure was determined, the mechanisms behind inheritance, information flow, and gene function fell into place. Overall the flow of information is depicted as: DNA --> RNA --> protein. Both DNA and RNA can be replicated (i.e. DNA is synthesized from DNA, and RNA from RNA). RNA can be made or transcribed from DNA. It is called transcription since the same type of "language" is used in DNA and RNA -- i.e. nucleic acids. In some cases RNA may be used to make DNA (i.e. "reverse transcription") using a particular enzyme called reverse transciptase. Protein is synthesized from RNA by translation. It is called translation, because essentially a different "language" is used -- i.e. amino acids (instead of nucleic acids). Once protein has been synthesized from RNA, the information is trapped. In other words, there is no known mechanism that allows information to flow back into RNA from protein. At least, that was what was thought. The recently discovered "prions" indicates that there is in fact a mechanism for a type of protein replication, and this goes against the central dogma. Essentially, the mechanism breaks down as follows. An organism (let's say, a human being), has a "wild type" protein (or a "normal" protein with a specific shape for its proper functioning), which is a homolog to a prion. When the human is infected, the prion interacts with the wild type homolog and causes it to misfold (i.e. the prion causes the wild type protein to change its shape into a prion). Thus, there is a simple mechanism by which certain proteins can replicate. However, this central dogma of information flow is still upheld to some degree.

Essentially the central dogma describes the following pathway: DNA makes RNA makes Proteins makes Cell. This suggests that life is traceable to DNA. Unfortunately, the information pathway is then shortened to DNA makes Cell, which ultimately leads to the belief omnis forma ex DNA (all form from DNA). To give a quick example, the molecular apparatus for either translation or transcription is very complex, and requires many different RNA molecules and proteins. DNA by itself cannot make a cell.

With the recent completion of the sequencing of the human genome, it appears to be a popular notion that we now have a map of a human being. The genome is often described as a "blue-print" for making a human (or other organism), however, this analogy is a bad one. The "genome as a blue-print" analogy is bad, because an organism is much more than just genes. Let's be clear: a genetic map is a map that shows where genes lie on chromosomes. However, it is the products of those genes that interact with each other in the context of a cell (or more appropriately, in the context of a whole organism -- unicellular or multicellular). A blue-print for a building is designed so that someone can point to one location on the map, and be able to find the actual location in the building. The blue-print shows where a particular thing is in relation to everything else. In eukaryotes, certain gene products are targetted to particular compartments within the cell (e.g. organelles, such as mitochondria, chloroplasts, golgi bodies, endoplasmic reticulum, etc). One might be able to predict where a particular gene product will go, based on the signal sequence that is encoded by the gene. However, a genetic map by itself cannot describe how gene products will interact with one another. Just because an organism is traceable to DNA, doesn't mean that the organism is created by DNA. Alternatively, just because life is traceable to the Big Bang, doesn't mean that the Big Bang created life (i.e. there were many other events that occurred between the Big Bang and the origin of life, such as the formation of atoms, stars, galaxies, planets, etc).

One of the tenets from cell theory directly opposes the gene-centric view: "all cells come from pre-existing cells". In general, this is true, but for the one exception of when life first arose on Earth. DNA alone cannot make a cell. DNA cannot even make a protein by itself. Other molecules are required, such as chaperones which direct the folding of large newly synthesized proteins. Ribosomes and proteins are required in the actual translation mechanism to make more proteins. Certain eukaryotic structures are inherited, but not encoded by any genes (i.e. organelles). In particular, mitochondria come from preexisting mitochondria. If all the mitochondria are removed from a cell, that cell can't make new mitochondria -- the mitochondrial structure is not encoded in any gene or any number of genes. The same is true for chloroplasts, the endoplasmic reticulum, centrioles, and golgi bodies. This is known as "structural inheritance" (or cytoplasmic inheritance).

Work by Sonneborn and others in the 1960s and 1970s demonstrated the importance of structural inheritance with ciliates (ref. 1). One example, is the inheritance of ciliary rows. Patches of ciliary rows were inverted 180 degrees on the cell surface of Paramecium. These inverted patches retained their normal structure, function, and development. They only differed in their orientation and they were inherited as such -- progeny had the same inverted regions of cilia. Ciliary number may also be inherited (e.g. 8 rows are inherited as 8 rows and 9 rows as 9 rows). Another example in Paramecium, is the inheritance of doublets and of singlets. Doublets (i.e. two cells permanently joined together) can form by the failure of conjugating cells to separate. Sonneborn showed that doublets are maintained as doublets, and singlets as singlets, and that the basis of this inheritance pattern resided in the cell cortex -- a phenomenon of structural organization, rather than of genetics.

Another point of opposition against the gene centric paradigm can arise from symbiosis. For example, elephants are made of much more than just "elephant cells" and "elephant chromosomes". Elephants also contain communities of microbes. These microbes are picked up from the environment, and not inherited through the germ line. The same is true for other metazoans (multi-cellular animals), as well as for other symbiotic relationships.

The notion that DNA is a blueprint (or a "program") for building an organism is simply inadequate to account for the assembly and maintenance of intracellular structures and their spatial organization. By way of analogy, a computer disk may contain written programs on it, but those programs are useless without a computer to run on. Gene products are made within the context of a cell, and in the context of the compartments of a cell. A cell has structural properties that are not encoded by any gene, even though genes may encode products (i.e. building blocks) for the maintenance of those structures. Gene theory is not sufficient in explanatory power to replace cell theory completely.

Fortunately, there is a relatively new field entering biology, which has been in the works since at least the 1970s (ref. ): proteomics. Genomics is the study of genes and genomes, whereas proteomics is the study of proteins (i.e. protein structure and function, and their interactions in an organism). Now that the human genome has been sequenced, research will focus on protein structures and interactions (primarily for the purpose of medically relevant information).